The present invention pertains generally to polymer matrices capable of drug delivery, for instance in tissue engineering applications, and more particularly to such polymer matrices that release drugs or a combination of drugs, such as growth factors, pharmaceuticals, genetic material, etc., in response to mechanical stimulation of the polymer matrix, for instance, compression or tension, induced by any of a variety of mechanisms.
An extracellular matrix (ECM) of noncellular material has been identified in many multi-cellular organisms, including-human beings. ECM molecules include specialized glycoproteins, proteoglycans, and complex carbohydrates. A wide variety of ECM structures have been identified, and ECM has been implicated in such biological processes as tissue formation.
Recently, tissue engineering has been widely researched. Tissue engineering is directed towards creating biological tissue rather than relying on scarce transplantable organs. Simply put, the method of tissue engineering is tissue and organ reconstruction using three-dimensional, polymeric matrices, also referred to as xe2x80x9cscaffoldsxe2x80x9d, which mimic a body""s ECM to provide a space for new tissue formation in vivo. One promising group of materials for making the three-dimensional polymer matrices for tissue engineering are hydrogels. Hydrogels have numerous other applications, including as food additives, blood contact materials, bioadhesives, contact lenses, wound dressings, artificial organs, controlled release formulations, membranes, superabsorbents, cell encapsulation and immunoisolation materials, and delivery carriers for bioactive agents, including drugs. A number of synthetic and naturally derived materials may be used in the formation of hydrogels, and one widely used material is alginate, a hydrophilic polymer derived from seaweeds. Alginate comprises a family of natural copolymers of xcex1-D-mannuronic acid and xcex2-L-guluronic acid. See Martinsen et al., Biotechnology and Bioengineering, 33: p. 79-89 (1989); Draget et al., Carbohydrate Polymers, 14: p. 159-178 (1991).
Delivery of growth factors from polymer matrices, such as artificial ECM""s, is one aspect of tissue engineering that has been the subject of recent research. See Shea et al., Nature Biotech, 17: p. 551-554 (1999); and Ripamonti et al., Crit. Rev. Oral Biol. Med., 8: p. 154-163 (1997). Natural ECM""s are repositories of various growth factors that are released to cells in surrounding tissue to impact a variety of physiological processes. For instance, the release of vascular endothelial growth factor (VEGF) has been shown to enhance the growth of endothelial cells and promote vascularization of growing tissues. See Neufelf et al., FASEB J., 13: 9-22 (1999). Similar drug delivery can be achieved from synthetic and naturally derived polymers. See Baldwin et al., Adv. Drug Delivery Rev., 33: 71-86 (1998). Most tissues in the body, both human and other animals, are subjected to mechanical stresses, such as occur in the compression of cartilage and muscle tensioning. In many instances, such as exemplified by muscle tensioning, these stresses are mediated by various chemical signals. In other circumstances, such as the compression of cartilage, the mechanical stress is induced by external loading (e.g., leg impact during walking or running). Yet, despite the dynamic conditions under which many body tissues function, drug delivery systems have been designed to operate under static conditions.
It would therefore be advantageous to provide a polymer matrix capable of drug delivery that improves upon conventional drug delivery mechanisms, and particularly one that is more ideally suited to deliver drugs, or combinations of drugs, to dynamic, in vivo environments.
The present invention relates to a polymer matrix composition, either naturally derived or synthetic, that is capable of releasing a desired drug or combination of drugs into a surrounding environment, including in vivo, when mechanically stimulated by any of a variety of mechanisms, including, without limitation, external loading and chemical signaling. The drug or combination of drugs are reversibly bound to the polymer matrix, so that release of the drug or combination of drugs from the polymer-matrix can be sustained over a period of time and is linked to the mechanical stimulation (e.g., compression, tensioning, etc.) of the polymer matrix. The invention is also directed to methods of drug delivery using the polymer matrix composition. Further aspects of the invention can be seen from reading the full disclosure, and the invention is not limited to specifically denoted aspects.
According to the method for drug delivery of this invention, a polymer matrix is provided having reversibly bound thereto a drug or combination of drugs, the polymer matrix being capable of releasing said drug or combination of drugs when the polymer matrix is mechanically stimulated; the polymer matrix can be delivered to an in vivo locus, including, by way of example, the site of a wound or trauma or disease or malfunctioning tissue in the body of an animal, including human, and mechanical stimulation, originating either outside of or within the animal body, is applied to the polymer matrix to effect release of the drug or combination of drugs in the area of the in vivo locus. As indicated, such mechanical stimulation can be effected by surrounding tissues, such as tensioning muscles, prompted by various chemical signals or other biological pathways. Alternatively, mechanical stimulation can be produced by external factors, for instance, external loading, electromagnetic signals, etc., that act directly on the polymer matrix, or that mediate mechanical stimulation of the polymer matrix by other means. As per one feature of this invention, feedback controlled external means can be employed to mediate the release of a drug or combination of drugs from the polymer matrices. This can take the form, for instance, of a patient-worn device adapted to produce a mechanical stimulation-inducing signal, such as an electromagnetic signal or chemical stimulant, conveyed to the locus of the polymer matrix to effect drug release directly or be mediating an internal mechanical stimulation.